Process for the synthesis of benzo[b]thiophenes

ABSTRACT

The present invention is directed to a new process for the synthesis of 2-aryl benzo[b]thiophenes, and to novel intermediates therefor.

BACKGROUND OF THE INVENTION

The present invention is directed to a new process for the synthesis ofbenzo[b]thiophenes, in particular 2-arylbenzo [b]thiophenes.

Benzo[b]thiophenes have been prepared by a number of different syntheticroutes. One of the most widely used methods is the oxidative cyclizationof o-mercaptocinnamic acids. This route is limited to the preparation ofbenzo[b]-thiophene-2-carboxylates. 2-Phenylbenzo[b]thiophenes areprepared by acid-catalyzed cyclization of 2-phenylthioacetaldehydedialkyl acetals. Unsubstituted benzo[b]thiophenes are prepared bycatalytic condensation of styrene and sulfur. 3-Substitutedbenzo[b]thiophenes are prepared by acid-catalyzed cyclization ofarylthiomethyl ketones; however, this route is limited to thepreparation of 3-alkylbenzo[b]thiophenes. See Campaigne, "Thiophenes andtheir Benzo Derivatives: (iii) Synthesis and Applications," inComprehensive Heterocyclic Chemistry (Katritzky and Rees, eds.), VolumeIV, Part III, 863-934 (1984). 3-Chloro-2-phenylbenzo[b]thiophene isprepared by the reaction of diphenylacetylene with sulfur dichloride.Barton and Zika, J. Org. Chem., 35, 1729-1733 (1970). Benzo[b]thiopheneshave also been prepared by pyrolysis of styryl sulfoxides. However, lowyields and extremely high temperatures make this route unsuitable forproduction-scale syntheses. See Ando, J. Chem. Soc., Chem. Comm.,704-705 (1975).

The preparation of 6-hydroxy-2-(4-hydroxyphenyl)benzo-[b]thiophenes wasdescribed in U.S. Pat. Nos. 4,133,814 and 4,380,635. One processdescribed in these patents is the acid-catalyzed intramolecularcyclization/rearrangement ofα-(3-methoxyphenylthio)-4-methoxyacetophenone. The reaction of thisstarting compound in neat polyphosphoric acid at about 85° C. to about90° C. gives an approximate 3:1 mixture of two regioisomeric products:6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene and4-methoxy-2-(4-methoxyphenyl)benzo[b]-thiophene. These isomericbenzo[b]thiophenes co-precipitate from the reaction mixture, producing amixture containing both compounds. To obtain a single regioisomer, theregioisomers must be separated, such as by chromatography or fractionalcrystallization. Therefore, there currently exists a need for anefficient and regiospecific synthesis of 2-arylbenzo[b]thiophenes fromreadily available starting materials.

SUMMARY OF THE INVENTION

The present invention is directed to a process for the synthesis ofbenzo[b]thiophenes. Specifically, the present invention is directed to aprocess for preparing a compound of the formula ##STR1##

wherein:

R¹ is hydrogen, C₁ -C₄ alkoxy, arylalkoxy, halo, amino; and

R₂ is hydrogen, C₁ -C₄ alkoxy, arylalkoxy, halo, amino; which comprisingtreating a compound of the formula ##STR2## wherein R₁ and R₂ are asdefined above, with an acid catalyst. The present invention is alsodirected to the formula VI compounds, as well as, processes for theirpreparation.

DETAILED DESCRIPTION OF THE INVENTION

The term "acid catalyst" represents a Lewis acid or a Br.o slashed.nstedacid. Representative Lewis acids are zinc chloride, zinc iodide,aluminum chloride, and aluminum bromide. Representative Bransted acidsinclude: inorganic acids, such as sulfuric and phosphoric acids;carboxylic acids, such as acetic and trifluorocetic acids; sulfonicacids, such as methanesulfonic, benzenesulfonic, 1-naphthalenesulfonic,1-butanesulfonic, ethanesulfonic, 4-ethylbenzenesulfonic,1-hexanesulfonic, 1,5-naphthalenedisulfonic, 1-octanesulfonic,camphorsulfonic, trifluoromethanesulfonic, and p-toluenesulfonic acids;and polymeric arylsulfonic acids, such as Nafion®, Amberlyst®, orAmberlite®. The preferred acids for use in catalyzing the processes ofthe present invention are sulfonic or polymeric sulfonic acids. Morepreferably, the acid catalysts are sulfonic acids, such asmethanesulfonic acid, benezenesulfonic acid, camphorsulfonic acid, andp-toluenesulfonic acid. The most preferred acid catalyst isp-toluenesulfonic acid.

In the above formula, the term "C₁ -C₄ alkoxy" represents groups such asmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and likegroups. The term "halo" refers to fluoro, chloro, bromo, or iodo groups.

The term "C₁ -C₆ alkyl" represents a straight or branched alkyl chainhaving from one to six carbon atoms. Typical C₁ -C₆ alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, n-pentyl, isopentyl, n-hexyl, 2-methylpentyl, and the like. Theterm "C₁ -C₄ alkyl" represents a straight or branched alkyl chain havingfrom one to four carbon atoms, and includes methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, i-butyl, and t-butyl.

The term "aryl" represents groups such as phenyl and substituted phenyl.The term "substituted phenyl" represents a phenyl group substituted withone or more moieties chosen from the group consisting of halo, hydroxy,nitro, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, trichloromethyl, andtrifluoromethyl. Examples of a substituted phenyl group include4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl,3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl,3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl,4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, 3-nitrophenyl,4-nitrophenyl, 2,4-dinitrophenyl, 4-methylphenyl, 4-ethylphenyl,4-methoxyphenyl, 4-propylphenyl, 4-n-butylphenyl, 4-t-butylphenyl,3-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6-difluorophenyl,2,6-dimethylphenyl, 2-fluoro-5-methylphenyl, 2,4,6-trifluorophenyl,2-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl,3,5-bis(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,3,5-dimethoxyphenyl, 4-hydroxy-3-methylphenyl, 3,5-dimethyl,4-hydroxyphenyl, 2-methyl-4-nitrophenyl, 4-methoxy-2-nitrophenyl, andthe like.

The term "arylalkyl" represents a C₁ -C₄ alkyl group bearing one or morearyl groups. Representatives of this group include benzyl,o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl (such as p-chlorobenzyl,p-bromobenzyl, piodobenzyl), 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, 4-phenylbutyl, 2-methyl-2-phenylpropyl,(2,6-dichlorophenyl)methyl, bis(2,6-dichlorophenyl)methyl,(4-hydroxyphenyl)methyl, (2,4-dinitrophenyl)methyl, diphenylmethyl,triphenylmethyl, (p-methoxyphenyl)diphenylmethyl,bis(pmethoxyphenyl)methyl, bis(2-nitrophenyl)methyl, and the like.

The term "arylalkoxy" represents a C₁ -C₄ alkoxy group bearing one ormore aryl groups. Representatives of this group include benzyloxy,o-nitrobenzyloxy, p-nitrobenzyloxy, p-halobenzyloxy (such asp-chlorobenzyloxy, p-bromobenzyloxy, p-iodobenzyloxy), 1-phenylethoxy,2-phenylethoxy, 3-phenylpropoxy, 4 -phenylbutoxy, 2 -methyl -2-phenylpropoxy, (2,6-dichlorophenyl) methoxy, bis (2,6-dichlorophenyl)methoxy, (4-hydroxyphenyl)methoxy, (2,4-dinitrophenyl)methoxy,diphenylmethoxy, triphenylmethoxy, (p-methoxyphenyl) diphenylmethoxy,bis (p-methoxyphenyl) methoxy, bis (2-nitrophenyl)methoxy, and the like.

The term "thermally-labile or acid-labile C₂ -C₁₀ alkyl, C₄ -C₁₀alkenyl, or aryl(C₁ -C₁₀ alkyl) group" represents a group that isreadily removed from the sulfoxide (SO) group under heating or bytreatment with the acid catalyst. The thermally-labile or acid-labile C₂-C₁₀ alkyl groups are straight or branched alkyl chains having from twoto ten carbon atoms and having at least one beta-hydrogen atom.Representative thermally-labile or acid-labile C₂ -C₁₀ alkyl groupsinclude ethyl, n-propyl, i-propyl, 1,1-dimethylpropoyl, n-butyl,sec-butyl, t-butyl, 1,1-dimethylbutyl, 2-methylbutyl, 3-methylbutyl,1-methylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,4-dimethylbutyl,3,3-dimethylbutyl, n-pentyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, n-hexyl, and the like. Thethermally-labile or acid-labile C₄ -C₁₀ alkenyl groups are straight orbranched alkenyl chains having from four to ten carbon atoms, at leastone site of unsaturation, and either a beta-hydrogen or delta-hydrogenatom. Representative thermally-labile or acid-labile C₄ -C₁₀ alkenylgroups include 2-butenyl, 3-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 2-methyl-3-butenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl,4-methyl-2-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,4-methyl-3-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,4-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and thelike. The term thermally-labile or acid-labile aryl (C₁ -C₁₀ alkyl)represents thermally-labile or acid-labile C₂ -C₁₀ alkyl groupsadditionally containing one or more aryl groups and aryl-substitutedmethyl groups. Representative aryl (C₁ -C₁₀ alkyl) groups includebenzyl, diphenylmethyl, triphenylmethyl, p-methoxybenzyl, 2-phenylethyl,2-phenylpropyl, 3-phenylpropyl, and the like.

The starting compounds for the compounds and processes of the presentinvention can be prepared by a number of routes. One method forpreparing the formula II compounds is shown in Scheme 1 ##STR3##

Generally, a formula VII compound is converted to a styryl sulfide byreaction with a mercaptan of the formula HSR₃ in the presence of a Lewisacid. The formula VIII compound is then oxidized to a styryl sulfoxide,a compound of formula II compound.

More specifically, a formula VII compound, wherein R₁ and R₂ are asdefined above, is treated with a Lewis acid, such as titanium(IV)chloride. This reaction is carried out in an anhydrous organic solvent,such as dry tetrahydrofuran, at a temperature of about 0° C. to about35° C. After about 15 minutes to about one hour, the reaction mixture istreated with an amine base and a mercaptan of the formula HSR₃, where R₃is a thermally-labile or acid-labile C₁ -C₁₀ alkyl, C₄ -C₁₀ alkenyl, oraryl(C₁ -C₁₀ alkyl) group. Preferably, the mercaptan and amine base areadded as a solution in the reaction solvent. A representative amine baseis triethylamine. After the addition of the mercaptan and amine base,the reaction is generally heated to a temperature of about 35° C. toabout 65° C., preferably at about 50° C. The products of this reactioncan be purified using techniques well known in the chemical arts, suchas by crystallization or chromatography.

The formula VIII compound, where R₁ and R₂ are as defined above and R₃is a thermally-labile or acid-labile C₂ -C₁₀ alkyl, C₄ -C₁₀ alkenyl, oraryl(C₁ -C₁₀ alkyl) group, is then oxidized to produce the formula IIcompounds. Suitable oxidizing agents for this reaction are peracids,such as peracetic acid and m-chloroperoxybenzoic acid, and hydrogenperoxide. This oxidation reaction is typically run in an organicsolvent, such as toluene, methylene chloride, chloroform, orcarbontetrachloride. When a peracid is used as the oxidant, the reactionis generally carried out at a temperature of about -30° C. to about 15°C., preferably at about -20° C. The products of the reaction are easilypurified by recrystallization. When R₃ is t-butyl, the crystallineproduct of this reaction sequence is the E regioisomer of formula II.

When R₃ has a tertiary carbon adjacent to the sulfur atom, the Zregioisomer of the formula II compounds can be prepared selectively by asecond route as shown in Scheme II. ##STR4##

Generally, a benzyl alcohol, a formula IX compound, is reacted with amercaptan of the formula R₃ SH to produce a benzyl sulfide, a formula Xcompound. This benzyl sulfide is reacted with a strong base, forming abenzylic anion, which is condensed with a benzaldehyde. Thiscondensation product is reacted with an acid chloride and the resultingintermediate treated with a second strong base to produce a styrylsulfide, a formula VIIIZ compound. This styryl sulfide is then oxidizedwith an oxidizing agent to produce the formula IIZ compound.

The first step in the synthesis of the Z styryl sulfoxide compounds isthe conversion of a benzyl alcohol to a benzyl sulfide, formula Xcompound. The reaction of the formula IX compound, where R₂ is asdefined above, with a mercaptan of the formula R₃ SH, wherein R₃ is athermally-labile or acid-labile C₂ -C₁₀ alkyl, C₄ -C₁₀ alkenyl, or aryl(C₁ -C₁₀ alkyl) group having a tertiary carbon atom adjacent to thesulfur atom, in the presence of a Lewis acid produces the benzylsulfide, a formula X compound. Suitable Lewis acids for thistransformation are zinc bromide, zinc chloride, zinc iodide, ferricchloride, titanium (IV) chloride, aluminum trichloride, and aluminumtribromide, preferably zinc iodide. The reaction is generally carriedout in an organic solvent, such as 1,2-dichloroethane or methylenechloride. When the reaction is carried out at room temperature, thereaction is complete after about 18 hours.

The benzyl sulfide is reacted with a strong base to form a benzylicanion. Suitable strong bases for this reaction include metal alkoxides,such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithiumt-butoxide, and potassium t-butoxide; sodium hydride; and alkyllithiums,such as n-butyllithium, t-butyllithium, sec-butyllithium, andmethyllithium. The preferred strong base for this reaction isn-butyllithium. The preferred solvent for this reaction is drytetrahydrofuran. When n-butytlithium is used as the strong base, thereaction is carried out at a temperature of about -35° C. to about -15°C.

The benzylic anion is condensed with a benzaldehyde to prepare anintermediate condensation product. The benzaldehyde has the generalformula p-R₁ (C₆ H₄)CHO, wherein R₁ is hydrogen, C₁ -C₄ alkoxy,arylalkoxy, halo, or amino. Preferably, the benzylic anion is preparedand the condensation product is formed in situ by adding thebenzaldehyde to the cold solution of the benzylic anion.

The condensation product is treated with an acid chloride to produce anintermediate compound. Representative acid chlorides include acylchlorides, such as acetyl chloride and benzoyl chloride; sulfonylchlorides, such as methanesulfonyl chloride, benzenesulfonyl chloride,1-butanesulfonyl chloride, ethanesulfonyl chloride, isopropylsulfonylchloride, and p-toluenesulfonyl chloride; alkoxycarbonyl chlorides, suchas methoxycarbonyl chloride and benzyloxycarbonyl chloride; anddialkylaminocarbonyl chlorides, such as N,N-dimethylaminocarbonylchloride; preferably a sulfonyl chloride. Preferably, methanesulfonylchloride is added to the reaction mixture shortly after formation of thecondensation product.

This intermediate compound is reacted with a second strong base toproduce a styryl sulfide, a formula VIIIZ compound where R₁, R₂, and R₃are as defined above. Suitable strong bases for this reaction includemetal alkoxides, such as sodium methoxide, sodium ethoxide, lithiumethoxide, lithium t-butoxide, and potassium t-butoxide; sodium hydride;alkyllithiums, such as n-butyllithium, t-butyllithium, sec-butyllithium,and methyllithium; and metal amides, such as sodium amide, magnesiumdiisopropylamide, and lithium diisopropylamide. The preferred strongbase for this reaction is potassium t-butoxide. Generally, this reactionis carried out at about 15° C. to about room temperature, preferably atroom temperature.

The styryl sulfide is oxidized to prepare the corresponding styrylsulfoxide. Suitable oxidizing agents for this reaction are peracids,such as peracetic acid and m-chloroperoxybenzoic acid; organicperoxides, such as t-butyl peroxide; and hydrogen peroxide. Preferablythe oxidizing agent is peracetic acid. This oxidation is typicallycarried out in an organic solvent, such as toluene, benzene, xylene,methanol, ethanol, methylacetate, ethylacetate, methylene chloride,1,2-dichloroethane, or chloroform; preferably methylene chloride. Thisoxidation can be carried out at a temperature of about -40° C. to about0° C.

Alternatively, when R₃ has a tertiary carbon adjacent to the sulfuratom, the benzyl sulfide intermediate (formula X compound) can be usedto produce a mixture of E and Z isomers of the styryl sulfoxides, theformula II compounds. This synthesis is outlined is Scheme 3. ##STR5##

The benzyl sulfide, prepared as described above, is oxidized to producethe corresponding benzyl sulfoxide. This benzyl sulfoxide is reactedwith a strong base, and the resulting anion condensed with abenzaldehyde. The condensation product is reacted with an acid chlorideand the resulting intermediate compound reacted with a second strongbase to produce the styryl sulfoxide.

The benzyl sulfide, the formula X compound, wherein R₂ is as definedabove and R₃ is a thermally-labile or acid-labile C₂ -C₁₀ alkyl, C₄ -C₁₀alkenyl, or aryl(C₁ -C₁₀ alkyl) group having a tertiary carbon atomadjacent to the sulfur atom, is oxidized to produce the correspondingbenzyl sulfoxide, formula XI compound. Suitable oxidizing agents forthis reaction are peracids, such as peracetic acid andm-chloroperoxybenzoic acid; organic peroxides, such as t-butyl peroxide;and hydrogen peroxide. Preferably the oxidizing agent is peracetic acid.This oxidation is typically carried out in an organic solvent, such astoluene, benzene, xylene, methanol, ethanol, methylacetate,ethylacetate, methylene chloride, 1,2-dichloroethane, or chloroform;preferably at a temperature of about -30° C. to about 5° C.

The benzyl sulfoxide, formula XI compound wherein R₂ and R₃ are asdefined above, is reacted with a strong base to produce a benzylicanion. Suitable strong bases for this reaction include metal alkoxides,such as sodium methoxide, sodium ethoxide, lithium ethoxide, lithiumt-butoxide, and potassium t-butoxide; sodium hydride; alkyllithiums,such as n-butyllithium, t-butyllithium, sec-butyllithium, andmethyllithium; and metal amides, such as sodium amide, magnesiumdiisopropylamide, and lithium diisopropylamide. The preferred base forthis transformation is n-butyllithium. This deprotonation reaction iscarried out in a dry organic solvent, such as tetrahydrofuran or1,2-dimethoxyethane, at a temperature of about -25° C.

The benzylic anion is condensed, without isolation, with a benzaldehydecompound of the formula p-R₁ (C₆ H₄)CHO, wherein R₁ is as defined above.Preferably, about one equivalent of the benzaldehyde is added to thecold solution prepared as described in the preceding paragraph. Theresulting diastereomeric mixture of condensation products may beisolated, or preferably used in the next step without isolation.

The condensation product is reacted with an acid chloride to produce anintermediate compound. The condensation product is optionally treatedwith a base, such as n-butyllithium, and reacted with an acid chloride.Representative acid chlorides include acyl chlorides, such as acetylchloride and benzoyl chloride; sulfonyl chlorides, such asmethanesulfonyl chloride, benzenesulfonyl chloride, 1-butanesulfonylchloride, ethanesulfonyl chloride, isopropylsulfonyl chloride, andp-toluenesulfonyl chloride; alkoxycarbonyl chlorides, such asmethoxycarbonyl chloride and benzyloxycarbonyl chloride; anddialkylaminocarbonyl chlorides, such as N,N-dimethylaminocarbonylchloride; preferably a sulfonyl chloride. The acid chloride is added tothe cold reaction mixture, then the resulting mixture is allowed to warmto room temperature. Preferably, methanesulfonyl chloride is added tothe reaction mixture shortly after formation of the condensationproduct, which eliminates the need to add additional base.

The resulting intermediate compound is reacted with a second strong baseto produce the E and Z styryl sulfoxides, formula II compounds where R₁,R₂, and R₃ are as defined above. Representative second strong bases forthis elimination reaction include metal alkoxides, such as sodiummethoxide, sodium ethoxide, lithium ethoxide, lithium t-butoxide, andpotassium t-butoxide; sodium hydride; alkyllithiums, such asn-butyllithium, t-butyllithium, sec-butyllithium, and methyllithium; andmetal amides, such as sodium amide, magnesium diisopropylamide, andlithium diisopropylamide. The preferred base for this transformation ispotassium t-butoxide. Preferably, a 20% excess, such as 1.2 equivalents,of the second base are added. Generally, this reaction is carried out ata temperature of about 15° C. to about room temperature, preferably atroom temperature.

The styryl sulfoxides are useful for the preparation of a benzothiophenestyryl sulfide as shown in Scheme 4. ##STR6##

These benzothiophene styryl sulfides, where R₁ and R₂ are as definedabove, are prepared from the styryl sulfoxides. Generally, a solution ofthe styryl sulfoxide, where R₁ and R₂ are as defined above and R₃ is athermally-labile or acid-labile C₁ -C₁₀ alkyl, C₄ -C₁₀ alkenyl, oraryl(C₁ -C₁₀ alkyl) group, is added to a solution of an acid catalyst ata temperature of about 100° C. to about 140° C., where the acid catalystis defined above. The concentration of acid catalyst is dependent on thefinal concentration of the formula II compound and the rate of additionof the formula II compound. When the styryl sulfoxide is at a finalconcentration of about 0.2M and is added over six hours, the acidconcentration is about 0.002M. When the styryl sulfoxide is at a finalconcentration of about 0.05M and is added over 30 minutes, the acidconcentration is about 0.025M. Significant quantities of the formula VIcompounds are present in the reaction after about one to two hours.Longer reaction times lead to the production of the formula I compounds.

These formula VI compounds may be subsequently converted to the formulaI compounds by treatment with additional acid, such as about 0.5 toabout three equivalents, and heating to about 100° C. to about 140° C.The concentration of the formula VI compound is in the range of about0.01M to about 0.5M. Suitable solvents for both the formation of theformula VI compounds and their conversion to formula I compounds includetoluene, xylene, and 1,2-dichloroethane.

The formula I compounds are useful as intermediates in the synthesis ofa series of 3-aroyl-2-arylbenzo[b]-thiophenes. U.S. Pat. Nos. 4,133,814and 4,418,068, which are incorporated herein by reference, describedthese 3-aroyl-2-arylbenzo[b]thiophenes, as well as methods for theirpreparation from the formula I compounds. An improved synthesis of agroup of these 3-aroyl-2-arylbenzo[b]-thiophenes from the formula Icompounds, wherein R₁ and R₂ are hydrogen, C₁ -C₄ alkoxy, or arylalkoxy,is outlined in Scheme 5. ##STR7##

The Formula I compound, wherein R₁ and R₂ are hydrogen, C₁ -C₄ alkoxy,or arylalkoxy, is acylated with the formula XII compound, wherein R₁₃ ischloro or hydroxy, in the presence of boron trichloride or borontribromide; boron trichloride is preferred. The reaction can be carriedout in a variety of organic solvents, such as chloroform, methylenechloride, 1,2-dichloroethane, 1,2,3-dichloropropane,1,1,2,2-tetrachloroethane, 1,2-dichlorobenzene, chlorobenzene, andfluorobenzene. The preferred solvent for this synthesis is1,2-dichloroethane. The reaction is carried out at a temperature ofabout -10° C. to about 25° C., preferably at 0° C. The reaction is bestcarried out at a concentration of the benzothiophene formula I compoundof about 0.2M to about 1.0M. The acylation reaction is generallycomplete after about two hours to about eight hours.

When R₁ and/or R₂ is a C₁ -C₄ alkoxy or arylalkoxy group, the acylatedbenzothiophene preferably is converted to a formula XIII compound,wherein R₅ and/or R₆ are hydroxy, without isolation of the product fromthe acylation reaction. This conversion is performed by addingadditional boron trichloride or boron tribromide and heating thereaction mixture. Preferably, two to five molar equivalents of borontrichloride are added to the reaction mixture, most preferably threemolar equivalents. This reaction is carried out at a temperature ofabout 25° C. to about 40° C., preferably at 35° C. The reaction isgenerally complete after about 4 hours to about 48 hours.

The acylation reaction or acylation/dealkylation reaction is quenchedwith an alcohol or a mixture of alcohols. Suitable alcohols for use inquenching the reaction include methanol, ethanol, and isopropanol.Preferably, the acylation/dealkylation reaction mixture is added to a95:5 mixture of ethanol and methanol (3A ethanol). The 3A ethanol can beat room temperature or heated to reflux, preferably at reflux. When thequench is performed in this manner, the Formula XIII compoundconveniently crystallizes from the resulting alcoholic mixture.Generally, 1.25 mL to 3.75 mL of alcohol per millimole of thebenzothiophene starting material are used.

The following examples further illustrate the present invention. Theexamples are not intended to be limiting to the scope of the inventionin any respect, and should not be so construed. All experiments were rununder positive pressure of dry nitrogen. All solvents and reagents wereused as obtained. The percentages are generally calculated on a weight(w/w) basis; except for high performance liquid chromatography (HPLC)solvents which are calculated on a volume (v/v) basis. Proton nuclearmagnetic resonance (¹ H NMR) spectra and ¹³ C nuclear magnetic resonance(¹³ C NMR) spectra were obtained on a Bruker AC-300 FTNMR spectrometerat 300.135 MHz or at 75,469 MHz for proton and carbon, respectively, ora GE QE-300 spectrometer at 300.15 MHz. Silica-gel flash chromatographywas performed as described by Still et al. using Silica Gel 60 (230-400mesh, E. Merck). Still et al., J. Org. Chem., 43, 2923 (1978). Elementalanalyses for carbon, hydrogen, and nitrogen were determined on a ControlEquipment Corporation 440 Elemental Analyzer. Elemental analyses forsulfur were determined on a Brinkman Colorimetric Elemental Analyzer.Melting points were determined in open glass capillaries on a Mel-TempII melting point apparatus, and are uncorrected. Field desorption massspectra (FDMS) were obtained using a Varian Instruments VG 70-SE or VGZAB-3F mass spectrometer. High resolution free atom bombardment massspectra (FABMS) were obtained using a Varian Instruments VG ZAB-2SE massspectrometer.

The in situ yields of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophenewere determined by high performance liquid chromatography (HPLC) incomparison to an authentic sample of this compound prepared by publishedsynthetic routes. See U.S. Pat. No. 4,133,814. Generally, samples of thereaction mixture was diluted with acetonitrile and the diluted sampleassayed by HPLC using a Zorbax® RX-C8 column (4.6 mm×25 cm) with UVdetection (280 nm). The following linear-gradient solvent system wasused for this analysis:

    ______________________________________                                        Gradient Solvent System                                                       Time (min)      A (%)   B (%)                                                 ______________________________________                                         0              50      50                                                     2              50      50                                                    20              20      80                                                    35              20      80                                                    37              50      50                                                    45              50      50                                                    ______________________________________                                         A: 0.01 M aqueous sodium phosphate (pH 2.0)                                   B: acetonitrile                                                          

The amount (percentages) of6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]thiophenehydrochloride in the crystalline material (potency) was determined bythe following method. A sample of the crystalline solid (5 mg) wasweighed into a 100-mL volumetric flask, and dissolved in a 70/30 (v/v)mixture of 75 mM potassium phosphate buffer (pH 2.0) and acetonitrile.An aliquot of this solution (10 μL) was assayed by high performanceliquid chromatography, using a Zorbax® Rx-C8 column (25 cm×4.6 mm ID, 5μparticle) and UV detection (280 nm). The following gradient solventsystem was used:

    ______________________________________                                        Gradient Solvent System (Potency)                                             Time (min)      A (%)   B (%)                                                 ______________________________________                                         0              70      30                                                    12              70      30                                                    14              25      75                                                    16              70      30                                                    25              70      30                                                    ______________________________________                                         A: 75 mM KH.sub.2 PO.sub.4 buffer (pH 2.0)                                    B: acetonitrile                                                          

The percentage of6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2piperidinoethoxy)benzoyl]benzo[b]thiophenehydrochloride in the sample was calculated using the peak area, slope(m), and intercept (b) of the calibration curve with the followingequation: ##EQU1##

The amount (percentage) of solvent, such as 1,2-dichloroethane, presentin the crystalline material was determined by gas chromatography. Asample of the crystalline solid (50 mg) was weighed into a 10-mLvolumetric flask, and dissolved in a solution of 2-butanol (0.025 mg/mL)in dimethylsulfoxide. A sample of this solution was analyzed on a gaschromatograph using a DB Wax column (30 m×0.53 mm ID, 1μ particle), witha column flow of 10 mL/min and flame ionization detection. The columntemperature was heated from 35° C. to 230° C. over a 12 minute period.The amount of solvent was determined by comparison to the internalstandard (2-butanol).

Example 1 E-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide A. Preparation ofE-t-Butyl 4,4'-Dimethoxystilbenyl Sulfide

A solution of desoxyanisoin (12.82 g) in tetrahydrofuran (100 mL) wastreated with titanium (IV) chloride (10.43 g). During the dropwiseaddition of titanium (IV) chloride, the reaction mixture was cooled tomaintain the temperature below 35° C. Upon complete addition, theresulting mixture was stirred at 30° C. After an additional 30 minutes,this mixture was treated with a solution of 2-methyl-2-propanethiol(6.76 mL) and triethylamine (16.70 mL) in tetrahydrofuran (15 mL). Theresulting mixture was stirred at 50° C. After two hours, the mixture wasadded to ten percent sodium carbonate (500 mL). The resulting mixturewas extracted with methylene chloride. The combined methylene chlorideextracts were dried over magnesium sulfate, filtered, and concentratedin vacuo to give 17.2 g of an oil, which crystallized upon cooling toroom temperature. This crystalline material was recrystallized from hotethanol to give 12.3 g of the title compound. Melting point 71°-73° C.

Analysis calculated for C₂₀ H₂₄ O₂ S: C, 73.13; H, 7.36; S, 9.76. Found:C, 73.37; H, 7.51; S, 9.87.

B. Preparation of E-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide

The crystalline compound prepared as described in Example 1A wasdissolved in toluene (150 mL), and the resulting solution cooled toabout -20° C. The cold solution was treated with peracetic acid (32% w/win dilute acetic acid, 1.24 g) over ten minutes. The resulting mixturewas extracted with saturated sodium sulfite and brine. The organic phasewas concentrated in vacuo. The residue was recrystallized from ethylacetate/heptane to give 14.11 g of the title compound. Melting point104° C. (dec).

Analysis calculated for C₂₀ H₂₄ O₃ S: C, 69.74; H, 7.02; S, 9.31. Found:C, 69.47; H, 7.04; S, 9.54.

Example 2 Z-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide A. Preparation oft-Butyl 4-Methoxybenzyl Sulfide

A mixture of 4-methoxybenzyl alcohol (10.13 g) and zinc iodide (11.7 g)in 1,2-dichloroethane (120 mL) was treated with 2-methyl-2-propanethiol(9.92 mL) in one portion. The resulting mixture was stirred at roomtemperature. After about 18 hours, the reaction was diluted with water(100 mL) and methylene chloride (100 mL). The organic phase was removed,dried over magnesium sulfate, filtered, and concentrated in vacuo togive 14.4 g of an oil.

¹ H NMR (CDCl₃): δ7.28 (d, 2H), 6.85 (d, 2H), 3.77 (s, 3H), 3.73 (s,2H), 1.36 (s, 9H).

¹³ C NMR (CDCl₃): δ130, 114, 56, 35, 32.

Analysis calculated for C₁₂ H₁₈ OS: C, 68.52; H, 8.63. Found: C, 68.80;H, 8.67.

B. Preparation of Z-t-Butyl 4,4'-Dimethoxystilbenyl Sulfide

A solution of the compound prepared as described in Example 2A (2.51 g)in tetrahydrofuran (50 mL) was cooled to about -20° C. This coldsolution was treated with a solution of n-butyllithium in hexane (1.6M,7.47 mL) over ten minutes. The resulting solution was allowed to warm toabout 0° C. over 35 minutes. This cold solution was treated withp-anisaldehyde (1.46 mL). After an additional 15 minutes, the reactionsolution was treated with methanesulfonyl chloride (0.95 mL). Theresulting reaction was allowed to warm to room temperature. After anadditional 45 minutes, the reaction mixture was treated with a solutionof potassium t-butoxide in tetrahydrofuran (1.0M, 12.0 mL). After anadditional 45 minutes, the reaction was quenched by the addition of 1Nhydrochloric acid (12.0 mL). The organic phase was separated, dried overmagnesium sulfate, filtered, and concentrated to an oil (4.4 g).

¹ H NMR (CDCl₃): δ7.95 (d, H), 7.05 (s, H), 6.9 (d, H), 6.8 (dd, 2H),3.75 (s, 3H), 0.95 (s, 9H).

¹³ C NMR (CDCl₃): 8153, 139, 137, 114, 56, 32.

C. Preparation of Z-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide

The compound from Example 2B was converted to the title compound usingthe procedure substantially as described in Example 1B.

¹ H NMR (CDCl₃): δ7.61 (d, H), 7.56 (d, H), 7.1 (s, H), 6.9 (dd, 2H),3.83 (s, 3H), 1.05 (s, 9H).

¹³ C NMR (CDCl₃): δ142, 132.5, 131, 118, 117, 56, 24.

Analysis calculated for C₂₀ H₂₄ O₃ S: C, 69.74; H, 7.02. Found: C,69.98; H, 6.94.

Example 3 E and Z-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide A.Preparation of t-Butyl 4-Methoxybenzyl Sulfide

A mixture of 4-methoxybenzyl alcohol (10.13 g) and zinc iodide (11.7 g)in 1,2-dichloroethane (120 mL) was treated with 2-methyl-2-propanethiol(9.92 mL) in one portion. The resulting mixture was stirred at roomtemperature. After about 18 hours, the reaction was diluted with water(100 mL) and methylene chloride (100 mL). The organic phase was removed,dried over magnesium sulfate, filtered, and concentrated in vacuo togive 14.4 g of an oil.

¹ H NMR (CDCl₃): δ7.28 (d, 2H), 6.85 (d, 2H), 3.77 (s, 3H), 3.73 (s,2H), 1.36 (s, 9H).

¹³ C NMR (CDCl₃): δ130, 114, 56, 35, 32.

Analysis calculated for C₁₂ H₁₈ OS: C, 68.52; H, 8.63. Found: C, 68.80;H, 8.67.

B. Preparation of t-Butyl 4-Methoxybenzyl Sulfoxide

A solution of the compound prepared as described in Example 3A (14.4 g)in 1,2-dichloroethane (50 mL) was cooled to about 5° C. and the coldsolution treated with peracetic acid (32% w/w in dilute acetic acid,14.2 mL) over 30 minutes. Upon complete addition of the peracetic acid,the reaction was treated with brine and sodium bicarbonate. The organicphase was removed, dried over magnesium sulfate, filtered, andconcentrated to a yellow precipitate. This residue was treated withhexane (100 mL) and the resulting mixture stirred at room temperature.After about 18 hours, the mixture was filtered and the solids washedwith hexane (100 mL). The solid material was dried in vacuo to give14.07 g of the title compound. Melting point 124°-126° C.

¹ H NMR (CDCl₃): δ7.26 (d, 2H), 6.89 (d, 2H), 3.79 (d, H), 3.78 (s, 3H),3.58 (d, H), 1.3 (s, 9H).

¹³ C NMR (CDCl₃): δ132, 114, 56, 53, 23.

Analysis calculated for C₁₂ H₁₈ O₂ S: C, 63.68; H, 8.02. Found: C,63.72; H, 7.93.

C. Preparation of E and Z-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide

A solution of the compound prepared as described in Example 3B (10.0 g)in tetrahydrofuran (140 mL) was cooled to about -30° to -25° C. (dryice/acetone bath). This cold solution was treated with n-butyllithium incyclohexane (1.6M, 27.65 mL) over 25 minutes. After stirring for 35minutes, the reaction mixture was treated with p-anisaldehyde (5.4 mL).The dry ice/acetone bath was removed and the reaction allowed to warm toabout 20° C. This mixture was treated with methanesulfonyl chloride (3.5mL). The temperature of the reaction rose from about 20° to about 35° C.upon addition of the methanesulfonyl chloride. The mixture was cooled toabout 25° C., then treated with potassium t-butoxide in tetrahydrofuran(1M, 50.9 mL). After stirring for an additional 35 minutes, the reactionwas treated with 1N hydrochloric acid (51.0 mL). The phases wereseparated, and the organic layer dried over magnesium sulfate, filtered,and concentrated to an oil (16.67 g). This material was used in the nextstep without further purification. The carbon and proton NMR spectrawere similar to that obtained for the compound prepared as described inExamples 1 and 2.

Example 4 E and Z-3-(4,4'-Dimethoxystilbenylsulfide)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene

A solution of p-toluenesulfonic acid monohydrate (552 mg) in toluene(111 mL) was heated to reflux, and water was removed by allowing it tocollect in a Dean-Stark trap.

A solution of the compound prepared as described in Example 1 (10 g) intoluene (34 mL) was added to the refluxing acid solution over six hours.After an additional two hours, the mixture was cooled to 0° C. After anadditional 18 hours, the cold mixture was filtered to remove theprecipitated 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene. Thefiltrate was extracted with an equal volume of saturated sodiumbicarbonate solution. The organic phase was separated, dried over sodiumsulfate, filtered, and concentrated in vacuo to give 4.8 g of an orangeoil. This oil was divided into two parts and each purified usingsilica-gel flash chromatography, eluting with hexane/ethyl acetate(3.5:1). The fractions contained in the desired regioisomers wereconcentrated to an oil. This oil was treated with diethyl ether toselectively crystallize the early-eluting regioisomer (155 mg). Themother liquor from these crystallizations were enriched in thelate-eluting regioisomer.

Early-eluting Isomer

¹ H NMR (CDCl₃): δ7.71 (d, 2H), 7.64 (d, 1H), 7.46 (d, 2H), 7.06 (d,1H), 6.94 (d, 2H), 6.92 (d, 2H), 6.90 (m, 1H), 6.85 (d, 2H), 6.59 (s,1H), 6.45 (d, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.66 (s,3H).

High resolution FABMS calculated for C₃₂ H₂₉ O₄ S₂ (MH⁺) 541.1507.Found: 541.1491.

Late-eluting Isomer

¹ H NMR (CDCl₃): δ7.90 (d, 1H), 7.62 (d, 2H), 7.24 (1H), 7.08 (d, 2H),7.02 (dd, 1H), 6.96 (d, 2H), 6.74-6.71 (d, 2H), 6.70 (d, 2H), 6.55 (d,2H), 6.21 (s, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.76 (s, 3H), 3.67 (s,3H).

FDMS: m/z=540 (m⁺)

Example 5 6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophene

The compound (early-eluting isomer) prepared as described in Example 4(125 mg) was added to a refluxing solution of p-toluenesulfonic acidmonohydrate (4.2 mg) in toluene (1.5 mL). After six hours,methanesulfonic acid (7.5 μL) was added to the reaction mixture. Afteran additional hour, the reaction mixture was allowed to cool to roomtemperature. The resulting mixture was diluted with acetonitrile andassayed by HPLC, showing a 71.1% in situ yield of the title compound.

Example 66-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo[b]thiopheneHydrochloride 1,2-Dichloroethane Solvate A. Preparation of Ethyl4-(2-Piperidinoethoxy)benzoate

A mixture of ethyl 4-hydroxybenzoate (8.31 g),1-(2-chloroethyl)piperidine monohydrochloride (10.13 g), potassiumcarbonate (16.59 g), and methyl ethyl ketone (60 mL) was heated to 80°C. After one hour, the mixture was cooled to about 55° C. and treatedwith additional 1-(2-chloroethyl)-piperidine monohydrochloride (0.92 g).The resulting mixture was heated to 80° C. The reaction was monitored bythin layer chromatography (TLC), using silica-gel plates and ethylacetate/acetonitrile/triethylamine (10:6:1, v/v). Additional portions of1-(2-chloroethyl)piperidine hydrochloride are added until the starting4-hydroxybenzoate ester is consumed. Upon complete reaction, thereaction mixture was treated with water (60 mL) and allowed to cool toroom temperature. The aqueous layer was discarded and the organic layerconcentrated in vacuo at 40° C. and 40 mm Hg. The resulting oil was usedin the next step without further purification.

B. Preparation of 4-(2-Piperidinoethoxy)benzoic Acid Hydrochloride

A solution of the compound prepared as described in Example 6A (about13.87 g) in methanol (30 mL) was treated with 5N sodium hydroxide (15mL), and heated to 40° C. After 41/2 hours, water (40 mL) was added. Theresulting mixture was cooled to 5°-10° C., and concentrated hydrochloricacid (18 mL) was added slowly. The title compound crystallized duringacidification. This crystalline product was collected by filtration, anddried in vacuo at 40°-50° C. to give 83% yield of the title compound.Melting point 270°-271° C.

C. Preparation of 4-(2-Piperidinoethoxy)benzoyl Chloride Hydrochloride

A solution of the compound prepared as described in Example 6B (30.01 g)and dimethylformamide (2 mL) in methylene chloride (500 mL) was treatedwith oxalyl chloride (10.5 mL) over a 30-35 minute period. Afterstirring for about 18 hours, the reaction was assayed for completion byHPLC analysis. Additional oxalyl chloride may be added to the reactionif the starting carboxylic acid is present. Upon completion, thereaction solution was evaporated to dryness in vacuo. The residue wasdissolved in methylene chloride (200 mL), and the resulting solutionevaporated to dryness. This dissolution/evaporation procedure wasrepeated to give the title compound as a solid.

D. Preparation of6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzol[b]thiophene Hydrochloride 1,2 -Dichloroethane Solvate

A mixture of the compound prepared as described in Example 5 (2.92 g),the compound prepared as described in Example 6C (3.45 g), and1,2-dichloroethane (52 mL) was cooled to about 0° C. Boron trichloridegas was condensed into a cold graduated cylinder (2.8 mL), and added tothe cold mixture described above. After eight hours at 0° C., thereaction mixture was treated with additional boron trichloride (2.8 mL).The resulting solution was heated to 35° C. After 16 hours, the reactionwas complete.

Methanol (30 mL) was treated with the reaction mixture from above over a20-minute period, causing the methanol to reflux. The resulting slurrywas stirred at 25° C. After one hour, the crystalline product wasfiltered, washed with cold methanol (8 mL), and dried at 40° C. in vacuoto give 5.14 g of the title compound. Melting point 225° C.

Potency (HPLC): 86.8%

1,2-Dichloroethane (gas chromatography): 6.5%

We claim:
 1. A compound of the formula ##STR8## wherein: R₁ is hydrogen,C₁ -C₄ alkoxy, arylalkoxy, halo, or amino; andR₂ is hydrogen, C₁ -C₄alkoxy, arylalkoxy, halo, or amino.
 2. The compound of claim 1wherein:R₁ is hydrogen, C₁ -C₄ alkoxy, or arylalkoxy; and R₂ ishydrogen, C₁ -C₄ alkoxy, or arylalkoxy.
 3. The compound of claim 2wherein:R₁ is hydrogen or C₁ -C₄ alkoxy; and R₂ is hydrogen or C₁ -C₄alkoxy.
 4. The compound of claim 3 wherein R₁ and R₂ are C₁ -C₄ alkoxy.5. The compound of claim 4 wherein R₁ and R₂ are methoxy.
 6. A processfor preparing a compound of the formula ##STR9## wherein: R₁ ishydrogen, C₁ -C₄ alkoxy, arylalkoxy, halo, or amino; andR₂ is hydrogen,C₁ -C₄ alkoxy, arylalkoxy, halo, or amino; which comprises reacting acompound of the formula ##STR10## wherein: R₁ and R₂ are as definedabove, and R₃ is a thermally-labile or acid-labile C₂ -C₁₀ alkyl, C₄-C₁₀ alkenyl, or aryl (C₁ -C₁₀ alkyl) group; with an acid catalyst at atemperature of about 100° C. to about 140° C., wherein the concentrationof the formula II compound is about 0.05M to about 0.2M.
 7. The processof claim 6 wherein:R₁ is hydrogen, C₁ -C₄ alkoxy, or arylalkoxy; and R₂is hydrogen, C₁ -C₄ alkoxy, or arylalkoxy.
 8. The process of claim 7wherein the acid catalyst is selected from the group consisting ofmethanesulfonic acid, benzenesulfonic acid, 1-naphthalenesulfonic acid,1-butanesulfonic acid, ethanesulfonic acid, 4-ethylbenzenesulfonic acid,1-hexanesulfonic acid, 1,5-naphthalenedisulfonic acid, 1-octanesulfonicacid, camphorsulfonic acid, trifluoromethanesulfonic acid,p-toluenesulfonic acid, Nafion®, Amberlyst®, and Amberlite®.
 9. Theprocess of claim 8 wherein the acid catalyst is selected form the groupconsisting of methanesulfonic acid, benzenesulfonic acid,camphorsulfonic acid, p-toluenesulfonic acid, Nafion®, Amberlyst®, andAmberlite®.
 10. The process of claim 9 wherein the acid catalyst isselected from the group consisting of methanesulfonic acid,p-toluenesulfonic acid, Nafion®, Amberlyst®, and Amberlite®.
 11. Theprocess of claim 10 wherein R₃ is a thermally-labile or acid-labile C₂-C₁₀ alkyl or aryl (C₁ -C₁₀ alkyl) group.
 12. The process of claim 11wherein R₃ is a thermally-labile or acid-labile C₂ -C₁₀ alkyl group. 13.The process of claim 12 wherein R₃ is t-butyl.
 14. The process of claim13 wherein R₁ and R₂ are C₁ -C₄ alkoxy.
 15. The process of claim 14wherein R₁ and R₂ are methoxy.
 16. The process of claim 15 wherein theacid catalyst is p-toluenesulfonic acid.